(a) Field of the Invention
The invention relates to the field of nanocapsule compositions having improved circulation times, uses thereof, and methods for preparing the same. The nanocapsule compositions of the present invention are adaptable to encapsulate agents of therapeutic interest, including macromolecules.
(b) Description of Prior Art
Hemoglobin (Hb) in red blood cells (RBC) is responsible for transporting oxygen. When extracted from a RBC, Hb can be sterilized to remove H.I.V. and other infective agents. Unfortunately, when the extracted Hb is infused into the body, it breaks down into dimers after infusion into the circulation of a recipient. Free Hb is also toxic especially for the kidney. Hemoglobin molecules can be chemically modified to prevent degradation after infusion. These simple modified hemoglobins are in the final stages of human testing. However, this type of modified hemoglobin is not covered by a membrane and as a result, it has to be ultra-pure to avoid adverse reactions. This also removes all the red blood cell enzymes that are needed to prevent the damaging effects of oxidants. Furthermore, the circulation half-time of modified hemoglobin in human is rather short, at approximately 24 hours.
Hemoglobin is but one example of the many biologically important macromolecules required by the body. In the event of illness, it is often desirable to supplement the body with macromolecules that are either lacking as a result of the illness or identified to have a therapeutic effect. Unfortunately, however, it has been difficult in the past to adequately deliver such macromolecules into the body in an acceptable manner to obtain the desired therapeutic effect.
In the past, attempts to microencapsulate hemoglobin for in vivo use have been made (Chang, T. M. S., 1964, Science 146, 524; Chang, T. M. S., 1997, “Blood Substitutes:Principles, methods, products and clinical trial”, vol. I, Karser publisher, Basel). Collodion, cellulose, HMDA (1,6-hexamethylenediamine), cross-linked protein, bilayer of phospholipid-cholesterol complexed on cross-linked protein membrane and other materials have been used to coat droplets of hemoglobin solution (Chang, T. M. S., 1997, “Blood Substitutes:Principles, methods, products and clinical trial”, vol. I, Karser publisher, Basel). However, these artificial cells with diameters of about one micron survived for a very short time in the host circulation following intravenous injections. Furthermore, the polymer membrane of these artificial cells accumulated in the body.
Emphasis then turned to the use of phospholipids in the preparation of liposomes containing hemoglobin (Chang, T. M. S., 1997, “Blood Substitutes:Principles, methods, products and clinical trial”, vol. I, Karser publisher, Basel). The use of submicron phospholipid-cholesterol microcapsules (liposomes) increased the survival time of hemoglobin in the circulation (Djordjevich, L. et al., 1980, Exp. Hematol. 8, 584). The drawback to these liposomes is their insufficient stability and strength and also the sensitivity of the phospholipid membranes to environmental degradation. Liposomes are subject to degradation during storage and while in host circulation. Furthermore, the lipid membranes are removed and accumulated in cells that are normally needed to remove bacteria and toxin from the circulation. As a result, the body's ability to fight infection and toxin can be markedly reduced.
Subsequently, a biodegradable polymer membrane containing hemoglobin was developed, as described in Applicant's U.S. Pat. No. 5,670,173, which is herein incorporated by reference. Here, a biodegradable polylactide membrane containing hemoglobin of about 150 nanometre diameter was prepared (T. M. S. Chang and W. P. Yu, U.S. Pat. No. 5,670,173 issued on Sep. 23, 1997). Polylactide can be readily converted to water and carbon dioxide after use and therefore does not accumulate in the body.
On average, after infusion, the polymer membrane as disclosed in U.S. Pat. No. 5,670,173 circulates with a half-time of less than 2 hours. It has been subsequently determined that for practical purposes, such as blood substitutes, for example, a biodegradable polymer membrane having a longer circulation half-time is preferred.
Accordingly, it would be highly desirable to be provided with a multi-purpose biodegradable nanocapsule having an improved in vivo circulation time.
It would also be highly desirable to be provided with a biodegradable nanocapsule having an effective circulation time of at least 6 hours.
It would be further desirable to be provided with a biodegradable nanocapsule having an effective circulation time of at least 14 hours.
It would be further desirable to be provided with a biodegradable nanocapsule having an effective circulation time of at least 24 hours.
It would be yet further desirable to be provided with a multi-purpose biodegradable nanocapsule that is selectively permeable to therapeutic agents of interest.
It would also be desirable to be provided with a multi-purpose biodegradable nanocapsule that is adaptable for the encapsulation of an agent of therapeutic interest, and delivery thereof in vivo.
It would be further desired to be provided with a nanocapsule composition adaptable to deliver an encapsulated agent of therapeutic interest in vivo with a controlled rate of release.